Obesity and insulin resistance are major causes of type 2 diabetes, which represents an enormous health burden to societies worldwide and is the fourth leading cause of death in most developed countries. Major perturbations associated with diabetes are abnormalities in calcium homeostasis and substrate metabolism, and induction of insulin resistance. Interestingly, disruption of endoplasmic reticulum (ER) Ca2+ levels has been demonstrated to trigger ER stress leading to the development of insulin resistance in obesity and diabetes conditions. A major cause of ER stress is disturbed calcium homeostasis caused by dysfunctional sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). In fact, SERCA2b activity and expression is diminished in animal models of obesity/diabetes. Upregulation of SERCA in liver of obese and diabetic mice via short term gene transfer reduced ER stress and improved glucose homeostasis. Thus, targeting dysfunctional SERCA2 pharmacologically will alleviate aberrant ER stress and associated disorders in diabetes. Using novel screening methodology, we have discovered a series of novel, drug-like small molecules that activate SERCA and rescue ER stress-induced cell death, are amenable to optimization for potency, and have enormous potential to treat diabetes. Preliminary results in animal models of diabetes show significant improvement in glucose tolerance, insulin sensitivity, hepatic steatosis and metabolism. In this proposal, we aim to conduct compound optimization of our novel series of allosteric SERCA activators and profile them more extensively to observe efficacy in in vivo models of diabetes, and to demonstrate that these novel SERCA activators rescue ER stress, improve glucose tolerance and restore insulin sensitivity. Our goal is to provide drug-like compounds suitable for development as novel therapeutic potential to treat diabetes.